The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The EGFR3 gene (c-erbB-1) is often amplified and overexpressed in malignant human tissues. Frequently, this amplification is correlated with structural rearrangement of the gene, resulting in in-frame deletion-mutants deficient in the intracellular and transmembrane domains of wild-type c-erb-1. One class of deletion-mutant identified in some malignant gliomas and non-small cell lung carcinomas is referred to as EGFRvIII. EGFRvIII is a mutation in which amino acids 6-273 (in the extracellular domain, with residue 1 being the residue immediately following the signal sequence) are deleted, and a glycine is inserted between residues 5 and 274. The sequence of the N-terminal 10 residues of the EGFRvIII mutation is LEEKKGNYVV (SEQ ID NO: 1).
Patients with EGFRvIII expressing breast cancers have detectable humoral and cellular immune responses against this peptide, suggesting that it serves as an immunogenic neo-antigen. A 13 amino acid peptide from this junction (LEEKKGNYVVTDH; SEQ ID NO: 2), referred to as PEPvIII, has been used to vaccinate humans with EGFRvIII-expressing tumors. In a recently published study, PEPvIII conjugated to KLH was administered to newly diagnosed glioblastoma multiforme (“GBM”) patients treated by gross total resection (>95%), radiation and temozolomide who had no radiographic evidence of progression. Humoral immune responses to EGFRvIII were observed in 6 of 14 immunized patients, while 3 of 17 showed a positive DTH response. The median overall survival for patients treated with vaccine and temozolomide was 26.0 months from the time of histologic diagnosis, versus 15.0 months for a matched cohort receiving only temozolomide. These encouraging results support the utility of EGFRvIII-expressing vaccines and suggest that a more potent vaccine, one that elicits a robust, durable and potent antigen-specific T cell response, could improve the magnitude and duration of the anti-EGFRvIII response.
Listeria monocytogenes is a gram-positive intracellular bacterium being explored for its utility as a vaccine vector. Infection with L. monocytogenes elicits a potent CD8+ T cell response, necessary for the killing of L. monocytogenes-infected cells and control of infection. Attenuation of L. monocytogenes improves the safety of the vector 100-1,000 fold while maintaining or enhancing its immunogenicity. The ease with which the vector can be genetically manipulated, together with the straightforward production methodologies make L. monocytogenes an attractive platform for cancer vaccines.
There remains a need in the art for compositions and methods for stimulating an effective immune response to of EGFRvIII-expressing maligancies.